The perineurium of frog sciatic nerve, which regulates nerve function, contains concentric cell layers that act as a diffusion barrier because of the presence of tight junctions. The cells have vesicles which take up extracellular lanthanum but do not form complete transcellular channels. Perineurial permeability is low to ions and water-soluble nonelectrolytes, but high to lipid soluble nonelectrolytes. There is no evidence of active ion transport. During Wallerian degeneration, perineurial permeability changes in relation to nerve function. The hydrostatic pressure in the endoneurium is positive and reflects the role of the perineurium as an osmotically active membrane. B. Fatique of single frog muscle fibers appears as a decline in tension output during prolonged tetanic stimulation. The concentration of ATP (energy source for contraction) remained normal in fatigued fibers. Furthermore, ATP is not unavailable for contraction, because it can be consumed in response to caffeine. We suggest that H+, as lactic acid, accumuates in fatigued fibers so as to interfere with excitation-contraction coupling.